Germline Pathogenic SMARCA4 Variants in Neuroblastoma

Authors

Leora Witkowski
Kim E Nichols
Marjolijn Jongmans
Nienke van Engelen
Ronald R de Krijger
Jennifer Herrera-Mullar
Lieve Tytgat
Armita Bahrami
Helen Mar Fan
Aimee L Davidson
Thomas Robertson
Michael Anderson
Martin Hasselblatt
Sharon E Plon
William D Foulkes

Publication Date

10-1-2023

Journal

Journal of Medical Genetics

DOI

10.1136/jmg-2022-108854

PMID

36813544

PMCID

PMC10570933

PubMedCentral® Posted Date

10-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Female, Humans, Infant, Male, Biomarkers, Tumor, Carcinoma, Small Cell, DNA Helicases, Germ-Line Mutation, Neuroblastoma, Nuclear Proteins, Transcription Factors, Child, Preschool, Child, Adolescent, Young Adult, Adult, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Pediatrics, Sequence Analysis, DNA

Abstract

Heterozygous germline pathogenic variants (GPVs) in SMARCA4, the gene encoding the ATP-dependent chromatin remodeling protein SMARCA4 (previously known as BRG1), predispose to several rare tumour types, including small cell carcinoma of the ovary, hypercalcemic type, atypical teratoid and malignant rhabdoid tumor, and uterine sarcoma. The increase in germline testing of SMARCA4 in recent years has revealed putative GPVs affecting SMARCA4 in patients with other cancer types. Here we describe 11 patients with neuroblastoma, including four previously unreported cases, all of whom were found to harbour heterozygous germline variants in SMARCA4. Median age at diagnosis was 5 years (range 2 months to 26 years), nine were males and eight of nine cases with tumour location information were in an adrenal gland. Eight of the germline variants were expected to result in loss of function of SMARCA4 (large deletion, truncating, canonical splice variants), while the remaining four were missense variants. Loss of heterozygosity of the wild-type SMARCA4 allele was found in all eight cases where somatic testing was performed, supporting the notion that SMARCA4 functions as a classic tumour suppressor. Altogether, these findings strongly suggest that neuroblastoma be included in the spectrum of SMARCA4-associated tumours.